What are the symptoms and management of Ehlers-Danlos Syndrome (EDS)?

Ehlers-Danlos Syndrome: Clinical Manifestations and Management

Core Clinical Features

Ehlers-Danlos syndrome presents with a defining triad: joint hypermobility with recurrent dislocations or subluxations, skin hyperextensibility, and tissue fragility. 1

Musculoskeletal Manifestations

• Joint hypermobility is the hallmark feature, confirmed using age-specific Beighton scale thresholds: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50 years, and ≥4/9 for adults over 50 years 1, 2
• Chronic joint and limb pain is extremely common, severe, and associated with significant functional impairment in daily activities 1, 3
• Recurrent joint dislocations and subluxations occur frequently, with pain severity correlating directly with the degree of hypermobility, number of dislocations, and previous surgical interventions 3
• Asthenic syndrome and kyphotic spinal deformity develop in 75% of cases 2

Dermatologic Features

• Soft or velvety skin with normal or slightly increased extensibility is characteristic 1
• Easy bruising without significant trauma is a key diagnostic feature 1, 4
• Tissue fragility leads to atrophic scarring and impaired wound healing 5, 6
• Skin hyperextensibility varies by subtype but is present across most EDS variants 7

Cardiovascular Complications

• Aortic root dilation occurs in 25-33% of hypermobile and classic EDS types, requiring echocardiographic surveillance 1, 2
• Vascular fragility is particularly severe in vascular type IV EDS, which carries the highest risk of spontaneous arterial and organ ruptures 1, 4

Gastrointestinal Manifestations

• Up to 60% of hypermobile EDS patients experience gastrointestinal symptoms, with up to 98% meeting diagnostic criteria for disorders of gut-brain interaction 2
• GI symptoms include abdominal cramping, nausea, vomiting, and diarrhea, particularly when associated with mast cell activation syndrome 8

Associated Conditions

• Postural orthostatic tachycardia syndrome (POTS) frequently coexists with hypermobile EDS, characterized by symptomatic heart rate increase of ≥30 beats/min within 10 minutes of standing without orthostatic hypotension 8
• Mast cell activation syndrome (MCAS) should be suspected when patients present with episodic symptoms involving 2 or more physiological systems (cutaneous, GI, cardiac, respiratory, neuropsychiatric), including pruritus, flushing, urticaria, wheezing, and tachycardia 8, 2

Additional Clinical Features

• High palate, joint hypermobility, and earlobe elasticity are observed in 63% of cases 2
• Sleep disturbances correlate with pain severity 3
• Severe fatigue is common and contributes independently to functional impairment 3

Diagnostic Approach

Physical Examination

• Perform Beighton scale assessment as the primary screening tool for joint hypermobility 1
• Evaluate skin texture and tissue fragility through palpation and assessment of scarring patterns 1
• Document any joint dislocations or subluxations 1

Cardiovascular Screening

• Obtain echocardiogram to evaluate for aortic root dilation in all patients with suspected EDS 1
• Perform dilated eye examination to exclude Marfan syndrome as an alternative diagnosis 1

Testing for Associated Conditions

• POTS testing should be targeted to patients with orthostatic intolerance symptoms through postural vital signs (active stand test or head-up tilt table test), not performed universally in all EDS patients 8
• MCAS testing with serum tryptase levels at baseline and 1-4 hours following symptom flares is indicated only when patients present with episodic multi-system symptoms; increases of 20% above baseline plus 2 ng/mL are diagnostic 8
• Refer to allergy specialists or mast cell disease centers for additional testing (urinary N-methylhistamine, leukotriene E4, 11b-prostaglandin F2) if MCAS is confirmed 8

Genetic Considerations

• Genetic testing should be performed before diagnosing hypermobile EDS, as 26.4% of clinically diagnosed cases have alternative genetic conditions 4
• Twelve of 13 EDS subtypes are monogenic with 19 identified causative genes, mostly related to collagen synthesis 1

Subtype Classification

Hypermobile Type (Most Common)

• Accounts for 80-90% of all EDS cases 1
• Characterized primarily by joint hypermobility and pain with systemic manifestations 2
• No specific genetic mutation identified yet 1

Vascular Type IV (Most Dangerous)

• Represents 5-10% of cases with prevalence of 1 in 100,000 to 1 in 250,000 4
• Poses the greatest mortality risk due to spontaneous arterial and organ ruptures 1
• Inherited in autosomal dominant pattern 4
• Invasive vascular procedures and diagnostic angiography are absolutely contraindicated due to risk of fatal complications 4

Management Principles

Surgical Considerations

• Surgical procedures carry significant risks due to tissue fragility 4
• Use retaining sutures and delay removal longer than usual to allow adequate healing 4
• Extend antibiotic prophylaxis until suture removal 4
• Expect slow wound healing and plan accordingly 4

Obstetric Management

• Pregnancy in vascular type IV EDS significantly increases risk of uterine or vascular rupture 4
• Most women with vascular EDS undergo cesarean delivery 4
• Anticipate postpartum hemorrhage 4
• Vascular ruptures can occur during pregnancy 4

Pain Management

• Pain treatment should be a prominent aspect of management, as pain is common, severe, and directly impacts functional capacity independent of fatigue levels 3
• Regular analgesic use is common among EDS patients 3

MCAS Treatment

• When MCAS is suspected or confirmed, treat with histamine receptor antagonists and mast cell stabilizers 2

Critical Pitfalls to Avoid

• Do not perform universal POTS/MCAS testing in all EDS patients; target testing only to those with specific clinical manifestations 8
• Never perform invasive angiography in patients with vascular collagen disorders 4
• Do not diagnose hypermobile EDS without genetic testing to exclude alternative diagnoses 4
• Do not underestimate pain severity—it is a major source of disability requiring aggressive management 3